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Randomized Controlled Trial
. 2020 Dec 4:11:605688.
doi: 10.3389/fimmu.2020.605688. eCollection 2020.

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience

Roberto Littera  1   2 , Marcello Campagna  3 , Silvia Deidda  4 , Goffredo Angioni  5 , Selene Cipri  1   6 , Maurizio Melis  3 , Davide Firinu  3 , Simonetta Santus  7 , Alberto Lai  7 , Rita Porcella  1 , Sara Lai  1 , Stefania Rassu  1 , Rosetta Scioscia  3 , Federico Meloni  3 , Daniele Schirru  3 , William Cordeddu  5 , Marta Anna Kowalik  8 , Maria Serra  9 , Paola Ragatzu  9 , Mauro Giovanni Carta  3 , Stefano Del Giacco  3 , Angelo Restivo  10 , Simona Deidda  10 , Sandro Orrù  9 , Antonella Palimodde  4 , Roberto Perra  4 , Germano Orrù  11 , Maria Conti  12 , Cinzia Balestrieri  12 , Giancarlo Serra  12 , Simona Onali  8 , Francesco Marongiu  3 , Andrea Perra  2   8 , Luchino Chessa  2   3   12
Affiliations
Randomized Controlled Trial

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience

Roberto Littera et al. Front Immunol. .

Abstract

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome.

Method and materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies.

Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024].

Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Keywords: COVID-19 severity; SARS-CoV-2 infection; Sardinian population; alleles; glucose-6-phosphate dehydrogenase; haplotypes; human leukocyte antigen; immunogenetic background.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The HLA alleles and haplotypes which confer susceptibility to or protection against SARS-CoV-2 infection. The figure shows the odds ratios (OR) for the significantly different frequencies observed for HLA alleles and haplotypes (HLA-B*40:02; HLA-C*04:01; HLA-A*30:02, -B*14:02; HLA-A*02:05, -B*58:01; HLA-A*30:02, -C*08:02; HLA-A*02:05, -C*07:01; HLA-A*02:05, -B*58:01, -C*07:01; HLA-A*30:02, -B*14:02, -C*08:02; HLA-A*02:05, -B*58:01, -DRB1*03:01; HLA-A*02:05, -B*18:01, -DRB1*16:01; HLA-A*02:05, -B*58:01, -C*07:01, -DRB1*03:01 and HLA-A*02:05, -B*58:01, -C*07:01, DRB1*16:01) in the two groups of COVID-19 patients and controls. The error bars, computed according to the two-tailed Fisher’s exact test, represent the 95% confidence intervals of the OR. The red line represents the threshold OR = 1 at which the HLA allele and haplotype frequencies in the two groups of patients and controls are equal.
Figure 2
Figure 2
Factors influencing the clinical course of COVID-19 in Sardinian patients. To establish which factors had a major influence on the clinical disease course, we compared asymptomatic/pauci-asymptomatic patients (Group A) to those with moderate or severe symptoms (Group S). Protective and risk factors were plotted against the odds ratio (OR). Age > 65 years, male gender, autoimmune disease, the HLA-A*30:02, B*14:02, C*08:02 haplotype, G6PDH deficiency, and the HLA-DRB1*08:01 allele conferred an increased risk for severe illness, whereas influenza vaccine (FLU vaccine), the HLA-A*02:05, B*58:01, C07:01, DRB1*03:01 haplotype, female gender, and the beta(0)39-thalassemia trait would seem to offer protection.
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